Increased Mortality in Young-Onset Parkinson's Disease.

OBJECTIVE: Few studies have followed Parkinson's disease (PD) patients from the time of diagnosis to the date of death. This study compared mortality in the Trondheim PD cohort to the general population, investigated causes of death and analyzed the associations between mortality and age at disease onset (AAO) and cognitive decline defined as Montreal Cognitive Assessment (MoCA) score below 26. METHODS: The cohort was followed longitudinally from 1997. By the end of January 2020, 587 patients had died. Comparisons to the Norwegian population were performed by calculating standardized mortality ratios (SMRs). Survival curves were estimated using the standard Kaplan-Meier estimator, and multivariable Cox proportional hazard models were estimated to investigate associations. RESULTS: SMR was 2.28 [95% confidence interval (CI): 2.13-2.44] for the whole cohort. For participants with AAO 20-39 years, the SMR was 5.55 (95% CI: 3.38-8.61). Median survival was 15 years (95% CI: 14.2-15.5) for the whole cohort. Early-onset PD (EOPD) patients (AAO < 50 years) had the longest median survival time. For all groups, there was a significant shortening in median survival time and an almost 3-fold higher age- and sex-adjusted hazard ratio for death when the MoCA score decreased below 26. CONCLUSION: PD patients with an AAO before 40 years had a more than fivefold higher mortality rate compared to a similar general population. EOPD patients had the longest median survival; however, their life expectancy was reduced to a greater degree than that of late-onset PD patients. Cognitive impairment was strongly associated with mortality in PD.

CSF total and oligomeric α-Synuclein along with TNF-α as risk biomarkers for Parkinson's disease: a study in LRRK2 mutation carriers.

BACKGROUND: Asymptomatic carriers of leucine-rich repeat kinase 2 (LRRK2) gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson's disease (PD). In this study, we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers. METHODS: We measured the levels of CSF total- (t-), oligomeric (o-) and phosphorylated S129 (pS129-) α-syn, total-tau (tTau), phosphorylated threonine 181 tau (pTau), amyloid-beta 40 (Aß-40), amyloid-beta-42 (Aß-42) and 40 inflammatory chemokines in symptomatic (n = 23) and asymptomatic (n = 51) LRRK2 mutation carriers, subjects with a clinical diagnosis of PD (n = 60) and age-matched healthy controls (n = 34). General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups. Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal PD. RESULTS: Discriminant function analysis revealed low levels of CSF t-α-syn, high levels of CSF o-α-syn and TNF-α best discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls. Assessing the discriminative power using receiver operating curve analysis, an area under the curve > 0.80 was generated. CONCLUSIONS: The current study suggests that CSF t-, o-α-syn and TNF-α are candidate risk biomarkers for the detection of PD at the prodromal stage. Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers' panel approach for an accurate and timely diagnosis of PD.

Clinical and Imaging Markers of Prodromal Parkinson's Disease.

The diagnosis of Parkinson's disease (PD) relies on the clinical effects of dopamine deficiency, including bradykinesia, rigidity and tremor, usually manifesting asymmetrically. Misdiagnosis is common, due to overlap of symptoms with other neurodegenerative disorders such as multiple system atrophy and progressive supranuclear palsy, and only autopsy can definitively confirm the disease. Motor deficits generally appear when 50-60% of dopaminergic neurons in the substantia nigra are already lost, limiting the effectiveness of potential neuroprotective therapies. Today, we consider PD to be not just a movement disorder, but rather a complex syndrome non-motor symptoms (NMS) including disorders of sleep-wake cycle regulation, cognitive impairment, disorders of mood and affect, autonomic dysfunction, sensory symptoms and pain. Symptomatic LRRK2 mutation carriers share non-motor features with individuals with sporadic PD, including hyposmia, constipation, impaired color discrimination, depression, and sleep disturbance. Following the assumption that the pre-symptomatic gene mutation carriers will eventually exhibit clinical symptoms, their neuroimaging results can be extended to the pre-symptomatic stage of PD. The long latent phase of PD, termed prodromal-PD, represents an opportunity for early recognition of incipient PD. Early recognition could allow initiation of possible neuroprotective therapies at a stage when therapies might be most effective. The number of markers with the sufficient level of evidence to be included in the MDS research criteria for prodromal PD have increased during the last 10 years. Here, we review the approach to prodromal PD, with an emphasis on clinical and imaging markers and report results from our neuroimaging study, a retrospective evaluation of a cohort of 39 participants who underwent DAT-SPECT scan as part of their follow up. The study was carried out to see if it was possible to detect subclinical signs in the preclinical (neurodegenerative processes have commenced, but there are no evident symptoms or signs) and prodromal (symptoms and signs are present, but are yet insufficient to define disease) stages of PD.

The accuracy of the clinical diagnosis of Parkinson disease. The HUNT study.

Diagnostic accuracy is crucial not only for prognostic and therapeutic reasons, but also for epidemiologic studies. We aimed to study the accuracy of the clinical diagnosis of Parkinson disease (PD) for participants in The Nord-Trøndelag Health Study (HUNT), a health survey, containing data from approximately 126,000 individuals and biological material from 80,000 individuals. We included 980 participants from the HUNT study diagnosed with PD or secondary parkinsonism/related parkinsonian disorders. The participants had been diagnosed in conjunction with admission to hospitals in Trøndelag or through out-patient examination. We validated the diagnosis of PD by reviewing available Electronic Health Records (EHRs) using the MDS Clinical Diagnostic Criteria as gold standard. In total 61% (601/980) of the participants had available EHRs and were selected for validation. Out of those, 92% (550/601) had been diagnosed with PD while 8% (51/601) had been diagnosed with secondary parkinsonism/related parkinsonian disorders. The main outcome measure was the accuracy of the clinical diagnosis of PD for participants in the HUNT study. We verified PD in 65% (358/550) and excluded PD in 35% (192/550) of the participants. According to our results, the overall quality of the clinical diagnosis of PD for participants in the HUNT study is not optimal. Quality assurance of ICD codes entered into health registers is crucial before biological material obtained from these populations can be used in the search of new biomarkers for PD.

Alterations in the reduced pteridine contents in the cerebrospinal fluids of LRRK2 mutation carriers and patients with Parkinson's disease.

Tetrahydrobiopterin (BH4) is a cofactor for tyrosine hydroxylase that is essential for the biosynthesis of dopamine. Parkinson's disease (PD) is characterized by a progressive degeneration of nigrostriatal dopaminergic neurons, and biomarkers reflecting the degree of neurodegeneration are important not only for basic research but also for clinical diagnosis and the treatment of the disease. Although the total neopterin and biopterin levels in the cerebrospinal fluids (CSF) of the patients with PD were reported, alterations in the composition of reduced and oxidized forms of pteridine compounds have not been examined. In this study, we first examined the time-dependent alterations in BH4 and other reduced pteridine compounds in the CSF of an MPTP-treated monkey as a primate PD model. We found that the CSF levels of BH4 and dihydroneopterin, an intermittent metabolite of BH4-biosynthesis, altered inversely with progression of neurodegeneration, whereas those of dihydrobiopterin and neopterin were relatively low and constant. Next, we assayed the amounts of reduced pteridine compounds in the CSF of 36 pre-symptomatic LRRK2-mutation (N1437H or G2019S) carriers (LRRK2-carrier), 13 patients with PD symptoms (LRRK2-PD), 46 patients with sporadic PD (sPD), and 26 non-PD individuals. The BH4 levels were significantly lower in both the LRRK2-PD and sPD patients, and the LRRK2-carriers exhibited higher BH4 levels compared with the sPD patients. The total neopterin levels in the CSF of the LRRK2-PD were significantly higher than those in the sPD and non-PD individuals, which indicated greater inflammatory responses in the brains of LRRK2-PD patients. The present results suggest that detailed analyses of pteridine levels in the CSF might be useful for understanding the pathophysiology of familial PD and for monitoring PD progression.